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Monday, May 31, 2010

Is homosexuality a lifestyle choice or an innate biological disposition?The idea that it is a choice is certainly widespread – a part of several mainstream religious doctrines and political ideologies – and is used to condone significant discrimination against homosexuals and the criminalization of homosexual behaviour.But what does the science say?

The broad conclusions are that sexual orientation is an innate disposition – no different from whether you are left or right-handed – that it is affected by genetic influences and that it reflects differences in brain structure and function.I will consider the evidence of genetic effects on sexual orientation here, including some recent additions – a later blog will look at the neurobiological findings.

A number of family and twin studies of the heritability of sexual orientation, starting in the 1950’s, found significant genetic influences: the statistical likelihood of an individual being homosexual increased somewhat if they had a homosexualdizygotic (fraternal) twin and dramatically if they had a homosexual monozygotic (identical) twin.However, these studies have generally suffered from some methodological limitations, including small sample sizes, the possibility of ascertainment bias due to the methods of recruitment of participants and an assumption that homosexuality in males and females is likely caused by the same mechanisms.

This assumption reflects a common idea that heterosexuality represents the same default state in both males and females – that it is the “normal”, baseline condition, one that requires no active processes.In fact, there is not a single rule: “be attracted to members of the opposite sex” – there are two rules: either be attracted to males or be attracted to females.These “rules” are embodied in anatomical and physiological differences in neural circuitry controlling sexual desire and behaviour, which differ between heterosexual males and females. (See: Wired for Sex for more on these processes in male brains).Understanding that both these behavioural rules require active and possibly distinct neurodevelopmental processes to establish makes it much easier to appreciate how alterations to those processes can lead to exceptions to how those rules are expressed.

Three recent twin studies have largely overcome previous methodological issues, demonstrate clear genetic influences on sexual orientation and argue strongly that homosexuality in males and females is due to distinct mechanisms.These studies all used large, population-based samples – that is, the subjects were not recruited to the study based on sexual orientation – in Sweden, Finland and Australia.In each study, rates of homosexuality were compared between pairs of monozygotic or dizygotic (same-sex or opposite-sex) twins.Each study had several thousand participants and several hundred twin pairs, making them well-powered statistically to detect genetic or environmental effects on sexual orientation.

These studies differed significantly in how they assessed sexual orientation, however, which may be reflected in their results.Zietsch and colleagues in the Australian study used a questionnaire to assess sexual attraction on a seven-point “Kinsey” scale, from exclusive heterosexual attraction to some degree of homosexual attraction.In response to this question, 11% of men and 13% of women, were rated as non-heterosexual.Alanko and colleagues in the Finnish study used a composite measure of same-sex attraction and same-sex sexual contact.In this survey,6.1% of men and 6.6% of women reported a homosexual orientation.Interestingly, the quantitative measures used demonstrated a much more bimodal distribution in males than in females, mirroring previous observations that bisexuality is much more common in females than in males (males tending to be either strongly heterosexual or strongly homosexual).Langstrom and colleagues used a direct question about lifetime number of same-sex sexual partners, with 5.6% of men and 7.8% of women reporting at least one – among those reporting at least one, men reported significantly more same-sex partners.

Estimates of genetic influences were high across all three studies.The Australian study found heritability of 48% for sexual orientation across males and females together.The Finnish study estimated genetic influences on sexual orientation of 45% and 50% for men and women, respectively.Neither study found any evidence of an effect of shared environment.The Swedish study gave somewhat different results – the heritability for male heterosexuality was quite high, 39%, with no effect of a shared environment.However, the estimated heritability for female heterosexuality was lower in this study, around 18-19%, and a significant contribution from the shared environment was found for females in this study (16-17%).These differences could reflect sampling effects, population genetic or cultural differences, or the differences in how sexual orientation was assessed (based on actual same-sex sexual behaviour in the Swedish study).It is important to note that a shared family environment for dizygotic twins includes a shared uterine environment, which may impact on neural development.

Importantly, both the Australian and the Finnish studies found zero correlation of homosexuality across opposite-sex dizygotic twin pairs, while same-sex dizygotic twin pairs showed substantial correlations.So, if a male has a fraternal twin brother who is homosexual, there is a significantly increased likelihood that he will also be.This is not the case if his twin sister is homosexual (and vice versa).

The major conclusion from these studies corroborates previous findings: sexual orientation is strongly influenced by genetics.Whatever the underlying biological processes, they are likely different for males and females, as reflected in differences in reports of same-sex attraction and expression of sexual behaviour, with males showing a more bimodal distribution.The potential neurobiological processes involved will be the subject of a later post.

Those are the scientific conclusions.My personal interpretation is that dispositional homosexuality is no more a choice than left or right-handedness.Most heterosexuals certainly can not point to the time when they “chose” to be straight no more than someone can say they chose to be right-handed.Natural left-handers can certainly learn to write right-handed but that will not change the inherent disposition, nor is there any good reason to try and change it.At the other extreme, these findings do not suggest that homosexuality is a biological “disorder”.Conditions are only defined as a disorder if they have a negative impact on someone’s life – by this definition, homosexuality is only a disorder if society’s reaction makes it one.

Monday, May 24, 2010

Most people know that strawberries are red, lemons are yellow and grass is green.And practically all adults can correctly identify the name of a colour when visually presented with it (allowing for some disagreements based on retinal pigment gene variants – more on that in a later post – and, yes, your wife is right, it’s green, not blue – just accept it).

The ability to recognise colours and remember which one goes with which object seems so trivial that it is hard to appreciate how specialised a skill it is – one that requires a lot of practice and which involves dedicated brain circuits.Children are able to visually discriminate between colours from a very young age and will readily separate objects by colour.However, they learn the names of colours with great difficulty, usually starting around the age of 3.At this stage, they will still frequently misidentify quite dissimilar colours, like red and blue.As they learn more colour names, they will only mix up ones that are more similar, like red and pink.They also have trouble picking out appropriately from inappropriately coloured objects – like picking which banana is the correct colour if shown one blue and one yellow one.

Part of the difficulty with colour is that it is completely unisensory and unlinked to any other information.Colour can’t be cross-checked with another sense in the way that form or texture can, for example.(This may be one reason why colour is such a common part of the “extra” perception in synaesthesia – it can be added to a sound or an odour without conflicting with the primary sensory information).In a way it’s remarkable that we can learn to so accurately categorise light of different wavelengths into specific colours, without any external reference point – after all, those of us without perfect pitch (the vast majority of the population) are not able to do that for musical notes of different frequency.

A rare condition called colour agnosia (or lack of knowledge of colours) sheds some light on how the brain categorises colours and how typical colours come to be attached to objects in our minds.As with other types of agnosia (including prosopagnosia, the lack of knowledge of faces), colour agnosia is characterised by normal processing of sensory information but an inability to categorise and assimilate this information – in essence, people with this condition have lost the concept of colour.For example, they will typically be perfectly able to separate objects by colour but be unable to name the colours, to pick out an example of a particular colour or to group distinct colours into related categories – hues of red, for example. They may, for example, be unable to remember what colour their car is – not just to name it, but also to pick it out of a colour palette.They do not readily incorporate colour into their “schema” of objects – though they may know, semantically, that the word grass and the word green are associated they will not associate the concept of green with the concept of grass.

This condition is all the more amazing for how specific it is – naming and knowledge of other types of stimuli or categories is typically unimpaired and the overall neuropsychological profile is unremarkable.Until a few years ago, only acquired cases of colour agnosia were known – caused by damage to a specific region of the brain, the left occipito-temporal region.This region is in the “ventral stream” of the visual system, where colour information is processed.It sits at a higher level in the hierarchy of processing than regions such as V4, where lesions cause the inability to perceive colour at all.

In 2007, Edward de Haan and colleagues reported a case of developmental colour agnosia.This was a man who showed all the classic deficits of colour agnosia but who claimed to have always had the condition.While he was referred to a neurology clinic following a stroke, this affected an area not involved in colour processing (in the cerebellum).He had otherwise no history of neurological insult or other abnormalities on an MRI scan.

Interestingly, this patient reported that his mother and daughter had the same problem.A follow-up study by the same authors confirmed this – both mother and daughter performed very poorly on selective colour knowledge tasks, while they were perfectly able to distinguish different colours.Now, I know what you’re thinking and you’re right – that might just mean that they never learned their colours in this family.Apart from the inherent implausibility of that idea (given that learning colours is also a part of early formal education) and the fact that the subjects had a full colour term vocabulary, the observation that the subject’s other daughter performed normally on all tasks argues strongly against that explanation.This suggests instead a genetic cause of this developmental form of colour agnosia.The authors speculate that it might involve the wiring of the colour knowledge area in the visual ventral stream.

This has yet to be tested, but if true, would be another example of a situation where altered wiring is thought to explain highly specific differences in the subjective representation of perceptual parameters.

Friday, May 14, 2010

The prevailing model for how the network of the brain is organized is the “small-world” network.In such a network, most units, or nodes, are very sparsely and only locally connected.However, a very small proportion of nodes, called hubs, are very highly connected, and over longer distances.These hubs thus provide an indirect but short pathway of connectivity between any two nodes in the network (like people with thousands of “friends” on Facebook).This overall architecture is highly efficient and robust and can be observed not just at the level of networks of neurons but also ata higher level of brain organization, in the pattern of connectivity of cortical areas.Indeed, it is also typical of genetic, social and many other networks, including the internet.

In the brain, the existence of hub neurons had thus been hypothesised, but these beasts had not actually been observed until a recent study by Rosa Cossart and colleagues.They were analysing the activity patterns of very large numbers of neurons in the developing hippocampus.At this stage, network activity in the hippocampus consists of fairly simple, large and rhythmic depolarisations, which are easily detected.(These oscillations are known to be crucial for the normal maturation of the network).

By observing the activity of large numbers of neurons over time, these researchers were able to examine which neurons in the network fired in synchrony with each other – these were deemed to be “functionally connected”.Most neurons were functionally connected with only a small number of other neurons in the network.However, a small subset was very highly connected – these neurons behaved like hubs in the network.The overall architecture fit the small-world model very well.

As well as recording the activity of the neurons they were also able to directly stimulate individual cells.Stimulating the sparsely connected neurons did not have much effect on the activity of the rest of the network.In contrast, stimulating the hub neurons had dramatic effects, directly activating many other neurons in the network and also affecting the synchrony of firing – in some cases greatly increasing it and in others completely abolishing it.

The hub neurons have several interesting properties: first, they are GABAergic – i.e., when they synapse on another cell they release the neurotransmitter GABA.In adults this tends to inhibit the activity of the recipient neuron, though in developing networks, GABA has excitatory effects.They also have very extensive axonal arborisations – they project over larger distances and make a greater number of and stronger synaptic connections than non-hub neurons. Finally, they are also more responsive to inputs and quicker to fire action potentials themselves, placing them in a position to orchestrate the responses of the entire network.

Though hub neurons have so far only been observed in the hippocampus it seems almost certain that they will also be found in the cortex, where their effects may be fundamental for the information processing capabilities of the brain.

Friday, May 7, 2010

Organisms with a bilaterally symmetric nervous system face a problem – how to integrate functions across the two sides so that behavioural outputs can be coordinated for the entire body.In the brain this is important to allow integration of the large number of cognitive “modules” which are differentially lateralised, such as language.(The importance of this communication is dramatically illustrated by so-called “split-brain” patients, who have had the majority of the connections between the two cerebral hemispheres severed in order to treat otherwise intractable epilepsy.These patients, first studied by Roger Sperry and colleagues, end up in essence with two brains inside the same skull, and it could be argued, two largely independent minds).

The importance of bilateral integration is also evident and very well understood in the control of movement, where motor commands have to be tightly and dynamically coordinated across the two sides of the body.The integration of the two sides of the nervous system is mediated by nerve fibres that project from one side to the other.Some neurons project axons across the midline and others do not – the binary nature of this choice has made it a favourite model system of developmental neurobiologists to investigate how growing axons are guided along specific pathways to their appropriate targets.As a result, a great deal is known about the cellular and molecular processes that control whether an axon will cross the midline.

The process is mediated by attractive and repulsive signals made by specialised cells which reside at the midline of the nervous system.(Interestingly, the study of such “chemotropic” molecules was also pioneered by Sperry in a set of seminal experiments in the frog visual system).These signals are detected by dedicated receptor proteins expressed on the surfaces of growing axons. The signals at the midline include two major families of secreted proteins: Netrins, which function to attract some neurons towards and across the midline, while repelling others, and Slits, which repel axons that normally do not cross the midline and which also prevent axons from re-crossing the midline multiple times.How each neuron responds to these cues depends on which receptors it expresses: DCC is a receptor protein for Netrins, while Robo proteins are receptors for Slits.Amazingly, all these proteins are very highly conserved, as are their functions in controlling axonal projections across the midline, which were discovered and elucidated in great detail in nematodes, fruit flies and mice.

A number of studies have shown that their functions are also conserved and equally crucial in humans.Elizabeth Engle and her colleagues found that mutations in the ROBO3 gene can lead to a condition with the unwieldy name of horizontal gaze palsy with progressive scoliosis (HGPPS).This syndrome is characterised by an inability to coordinate the lateral movement of the eyes in the horizontal plane.Lateral eye movements are controlled by the abducens-oculomotor nerves, one on each side of the head.The coordination of these movements of the two eyes is mediated by a set of interneurons which normally project across the midline of the hindbrain, where the cell bodies that form these nerves are located, and coordinate the activity of the nerves on the two sides.

As the ROBO3 gene is known to be required for axons to cross the midline, the implication was that the defect resulted from a failure to connect these cranial nerve nuclei on the two sides.A recent study by Alain Chedotal and colleagues modeling the effects of Robo3 mutations in mice strongly supports this explanation – deletion of the gene in just that part of the hindbrain did indeed disrupt connectivity between the two sides and resulted in similar defects in horizontal eye movements in the mice.

(If you’ve been paying attention you may be surprised that mutations in a Robo gene should cause a failure of axons to cross the midline – if the normal role of the Slit signals to which they respond is to keep axons on their own side, then mutation of a Robo gene should cause extra axons to cross the midline.This is true for the other two Robo genes – Robo3 performs a different role, down-regulating the responses of the other Robo proteins and so mutating it has the opposite effect).

Another study just published by Guy Rouleau and colleagues shows that the function of DCC in establishing trans-midline connectivity is also essential in humans.They found mutations in this gene in patients with Congenital Mirror Movements.These are involuntary movements of one side of the body that occur in response to voluntary movement of the other side – i.e., a failure to independently control and coordinate the two sides.A similar effect has been seen in mice with mutations in this gene, which are called “Kanga” mice because of their unusual hopping gait, caused by moving both hindlimbs at the same time.The mirror movements could be caused by a failure to project across the midline of interneurons in the spinal cord that normally inhibit movement of one side when the other side is moving.

These studies provide a dramatic example of the importance of bilateral integration in the control of movement. It will be interesting to investigate whether patients with these disorders also show any differences in cognitive domains which might relate to subtly altered connectivity of the two cerebral hemispheres.